Intrachromosomal recombination in tumour suppressor genes in cancer

Genomic deletions occur in tumour suppressor genes and genes regulating cell proliferation and such mutations are encountered frequently in the pathogenesis and progression of cancer. As discussed elsewhere in this book (see Chapter 3), homologous and non-homologous intrachromosomal recombination or unequal exchanges and recombination between chromatids can bring about the duplication of genetic material, which is often visualised as HSRs or DMs. Drug resistant cell lines contain DMs and HSRs, which represent amplification of the multi-drug resistance gene. These DMs not only contain amplified DNA but they also harbour Alu repeats (Sognier et al., 1994), and one could tacitly assume that Alu might have played some part in the amplification process. The BRCA1 gene is associated with susceptibility to develop breast and ovarian cancer. It may be described as a classical suppressor gene, shows LOH in cancer families and somatic mutations may also occur in breast and ovarian cancers. The wild-type gene appears to act as a negative regulator of tumour cell proliferation and growth, and its expression might be altered in tumour progression. The predisposition to develop cancer is related to mutations and the abrogation of suppressor function of the gene. The BRCA1 protein is a zinc finger protein and therefore might participate in the regulation of gene transcription. Germ-line mutations of BRCA1 seem to result in total loss of transcription or lead to the production of a truncated product, which might be functionally impaired. BRCA1 mutations and deletion mediated by Alu repeats occur in a significant proportion in families susceptible to breast and ovarian cancer. A deletion of I4kb fragment encompassing exons la and lb involving transcription start sites, and exon 2 was reported in a family carrying mutation of BRCA1. The deletion seemed to result from an unequal crossover of Alu repeats (Swensen et al., 1997). Rohlfs et al. (2000) have found a 7.1 kb germline deletion in two families with breast and ovarian cancer. The deletion of exons 8 and 9 occurs as a result of homologous recombination between an Alu repeat in intron 7 with one in intron 9, leading to a frame-shift mutation. Another frame-shift mutation in BRCA1 occurs as the result of a 3-kb exon 17 deletion, again with the apparent involvement of two closely related Alu repeats (Montagna et al., 1999). However, Payne et al. (2000) reported that a complex mutation consisting of an inverted duplication and deletion in the gene was not identified with any breakpoints and homologous recombination at Alu repeats.

Germ-line mutations of the APC gene are a significant feature of hereditary colon carcinoma. APC is a tumour suppressor gene and truncating mutations of this gene are associated with the early stages of colon cancer progression. The APC protein might interact with the transmembrane cell adhesion protein cadherin and, therefore, APC protein might also be involved together with cadherin in intercellular adhesion as well as in the signal transduction pathway (Sherbet and Lakshmi, 1997; Sherbet, 2001). Alu repeats seem to be involved in many APC mutations. Su et al. (2000) have found a large number of APC mutations in FAP families, rearrangements and deletions that appear to result from homologous or non-homologous recombination involving Alu repeats. A truncating mutation of APC is caused by the insertion of a 337-bp Alu into codon 1526 and the insertion has a poly (A) tail at the 3' end, which suggests that the insertion occurs by retroposition (Hailing et al., 1999).

The nm.23-HI and H2 genes, which code for nucleoside diphosphate (NDP) kinases, have been regarded as putative metastasis suppressor genes. These genes are human homologues of nm23 first identified as a suppressor gene in murine tumours. The levels of expression of nm23 or the NDP kinase show an inverse correlation with metastatic behaviour in many experimental tumour models as well as in human cancers. Equally there is much disagreement about the metastasis suppressor function of nm23 (see Sherbet, 2001). Lau et al. (1997) propagated NSCLC tissue by serial subcutaneous transplantation of primary tumours as well as their metastatic deposits. They state that nm.23-HI and H2 were detected in early passages of the tumours, but the genes seemed to be deleted in later passages. The genes were deleted in all metastatic propagation. The authors also noticed that human Alu sequences had also been deleted in the tumours that had lost nm.23■ This implicates Alu repeats in the deletion of nm.23. However, it might be well to remember that the loss of nm23 could be due to other recombination events. For Lau et al. (1997) found that mouse DNA had been incorporated into the NSCLC grafts.

The 13ql4 locus harbours a number of tumour suppressor genes that have been implicated in the pathogenesis of leukaemias. LOH or homozygous loss of 13ql4 occurs in a majority of CLL and also in mantle-cell lymphomas and multiple myeloma. Bullrich et al. (2001) have sequenced a 790 kb segment corresponding to the region harbouring putative suppressor genes related to CLL pathogenesis. They found that the centromeric section of this region contained twice as many Alu sequences as LINE1 elements, whilst in contrast LINE1 elements were preponderant in the telomeric section. The congregation of most known suppressors at the centromeric section of the locus suggest the possibility that the preponderance of Alu elements in this region might have had a bearing on the genetic stability of the region leading to genetic alterations or loss.

The loss of chromosome 3p is a frequent occurrence in cancer of the lung, breast, kidney and ovaries, and in cervical and head and neck cancers. Chromosome 3p contains many suppressor genes such as the von Hippel-Lindau (VHI.) gene, FHIT, TGFfi-RII and the RASSF1A gene of the ras domain family. The FHIT gene has been putatively attributed with tumour suppressor function, or at any rate, its loss appears to confer a proliferative advantage on cells that have forfeited FHIT expression. The FHIT locus, 3pl4.2, encompasses the fragile site FRA3B. The reason for mentioning this gene is simply to point out the operation of the LINE elements rather than the Alu in a large deletion in this gene. Nine out of 10 allelic deletions resulted in the loss of exon 7, and in 7 deletions the breakpoints occurred close to LINE elements, but no Alu sequences were involved (Mimori et al., 1999). Nevertheless, it seems possible that genetic instability might result from contribution of both Alu and LINE elements. This is exemplified by the 13ql4 locus where Alu and LINE1 repeats are only modest, around 20% as compared with other genomic sites, with Alu composing as high as 56% (International Human Genome Consortium, 2001), suggesting a potential loss of equilibrium between them in the generation of instability (Bullrich et al., 2001).

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